1. Field of Commercial Utilization
This invention relates to a process for producing an intermediate of a new quinolone compound useful as an intermediate of an anti-fungus agent, etc.
2. Description of the Related Art
7-(1a,5a,6a)-(6-Amino-3-azabicyclo[3,1,0]hexa-3-yl)-1-(2,4-difluorophenyl)- 6-fluoro-1,4-dihydro-4-oxo-1,8-naphtylidine-3-carboxylic acid expressed by the formula (V) ##STR3## (Development No. CP-99,219 (U.S. Pat. No. 5,164,402 and U.S. Pat. No. 5,256,791), has a broad anti-fungus spector, and has been greatly expected as a new quinolone synthetic anti-fungus agent of the next generation.
As to the method of synthesizing an intermediate constituting the side chain of this compound, expressed by the formula (VI): ##STR4## the following two representative preparation methods have been known:
the first method (1) is as follows: ##STR5##
Namely, an azabicyclo ring is formed from ethyl diazoacetate and N-benzylmaleimide as starting materials, followed by reducing the carbonyl group with lithium aluminum hydride, changing the benzyl group to benzyloxycarbonyl group, oxidizing the hydroxyl group at the 6-position, to a carboxylic acid, further carrying out a Curtius rearrangement, and finally removing the protective group (U.S. Pat. No. 5,164,402).
The second method (2) is as follows: ##STR6##
Namely, an azabicyclo ring core is formed from bromonitromethane and N-benzylmaleimide in the presence of a base, followed by reducing the carbonyl group with borane-THF, reacting the nitro group in the presence of zinc to convert it into an amino group, and finally protecting the amino group with a t-butyloxycarbonyl group (U.S. Pat. No. 5,256,791).
However, as to the method (1), ethyl diazoacetate which is highly explosive and limited in commercial availability, must be used as a starting material, and further, lithium aluminum hydride and Jone's reagent which are not easy to deal with in large quantities during the subsequent steps, are used, hence it is very difficult to commercially utilize the method.
Further, as to the method (2), although any of the steps subsequent to the formation of the azabicyclo ring have a high yield and a high efficiency; the efficiency of the ring formation from bromonitromethane and N-benzylmaleimide at the first step is as low as 17%; hence the efficiency through the total steps is reduced. Further, the bromonitromethane as the starting substance is explosive; hence its dealing is accompanied with difficulty. Namely, either of the methods could not have been regarded as a sufficient production process for obtaining the objective substance.
Problem to be Solved by the Invention
The present inventors have made extensive research related to these problems. As a result, we have found that when a cyclopropane tricarboxylic acid triester represented by the formula (I) as a starting substance is hydrolyzed, followed by dehydration condensation to obtain an acid anhydride (II), condensing this compound with an amine compound, to obtain a compound represented by the formula (III) as an intermediate, reducing its carbonyl group, to obtain an azide compound, and subjecting it to Curtius rearrangement, then an intermediate of a new quinolone compound represented by the formula (IV) can be obtained with a high yield. Thus, the present invention has been completed.
As apparent from the foregoing, the object of the present invention is to provide a process for producing a compound represented by the structural formula (IV) as a useful new quinolone compound intermediate.